PPARα Activation Attenuates Right Ventricular Hypertrophy by Regulating Myocardial Glucose and Lipid Metabolism in High-Altitude Pulmonary Hypertension In Vivo and In Vitro.
TL;DR
It is demonstrated that PPARα exerts a protective effect against RVH, at least in part, by promoting fatty acid oxidation through upregulation of its downstream target proteins CPT-1 and acyl-CoA oxidase 1.
Abstract
Zhang, Xiaoying, Jiajia Wu, Yuchan Zhang, Yuquan Xie, Qi Si, Shadi Li, and Yiwei Han. PPARα activation attenuates right ventricular hypertrophy by regulating myocardial glucose and lipid metabolism in high-altitude pulmonary hypertension in vivo and in vitro. High Alt Med Biol. 00:00-00, 2026.
Background
Right ventricular hypertrophy (RVH) and cardiac function are key prognostic determinants in patients with high-altitude pulmonary hypertension. Meanwhile, their initiation and progression are driven by disturbances in glucose and lipid metabolism in cardiomyocytes.
Objective
This study established an SU5416-associated hypobaric hypoxia-induced RVH (H-RVH) rat model and a CoCl2-induced hypoxic cardiomyocyte model to explore glucose and lipid metabolism alterations and mechanisms.
Methods
The metabolomic cluster analysis of metabolites primarily focused on lipid metabolism, along with Kyoto Encyclopedia of Genes and Genomes-enriched pathways, including glycolysis/gluconeogenesis, glycerophospholipid metabolism, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway.
Results
Compared with the control group, glucose transporter-4 (GLUT-4) and pyruvate dehydrogenase (PDH) kinase were increased by 320% and 220% in H-RVH rats, respectively (p < 0.05), whereas PDH and citrate synthase (CS) were decreased by 39% and 58%, respectively (p < 0.05), collectively indicating a shift toward glycolysis and away from glucose oxidation. Seahorse Extracellular Flux (XF) assay revealed that basal glycolysis and compensatory glycolytic capacity were significantly elevated in the CoCl2-induced hypoxic cardiomyocyte model compared with the control group (288.5 ± 9.82 vs. 344.1 ± 10.24, 335.9 ± 11.58 vs. 385.7 ± 14.74, p < 0.05). The expression levels of PPARα and carnitine palmitoyltransferase 1α (CPT-1α) in the H-RVH group were 48% and 56% lower than those in the control group, respectively (p < 0.05); acetyl-CoA and adenosine triphosphate (ATP) were also reduced (p < 0.05). Fenofibrate mitigated CoCl2-induced hypoxic damage through 1.6-fold activation of PPARα. Cardiac-specific PPARα overexpression via an adeno-associated virus (AAV9) effectively attenuated RVH, as evidenced by the reduction in Fulton's index (0.37 ± 0.09 vs. 0.46 ± 0.02, p < 0.05), right ventricular anterior wall diastolic (RVAWd) (0.64 ± 0.04 vs. 0.93 ± 0.02, p < 0.01) and RVAWs (0.68 ± 0.05 vs. 0.97 ± 0.02, p < 0.01). In contrast, PPARα knockdown did not significantly alter the Fulton index but markedly increased both RVAWd (1.00 ± 0.01 vs. 0.77 ± 0.03, p < 0.01) and RVAWs (1.00 ± 0.02 vs. 0.70 ± 0.05, p < 0.01).
Conclusion
In this study, our findings demonstrate that PPARα exerts a protective effect against RVH, at least in part, by promoting fatty acid oxidation through upregulation of its downstream target proteins CPT-1 and acyl-CoA oxidase 1.
